In response to an RFA from the National Institute of Neurological Disorders and Stroke, we propose to establish a Cincinnati Center for Neurofibromatosis Research. Our goal is to identify and therapeutically target signaling pathways that underlie peripheral nerve tumors resulting from NF1 loss of function. To accomplish this goal we have brought together three groups to attack NF1 tumors with genetic, molecular and cellular approaches to preclinical testing. In Project 1, George Thomas &Sara Kozma will investigate the contribution of the RAF, PI3K and PKA signaling pathways in the development of NF1, whether the effects of these pathways are mediated through constitutive activation of S6K1, and the impact of novel pharmacological inhibitors in models of NF1 in cell culture and in the mouse. Working closely with John Perentesis this group will initiate combinatorial studies of drugs first in cell based viability assays, then in xenografts as translational models for human clinical studies. In Project 2, Nancy Ratner uses these same models and new mouse strains to test the novel hypothesis that apparently non-Ras signaling in NF1 can actually be attributed to the Ras-related protein TC21, and use the same drugs tested in Project 1 for their ability to block cell migration. TC21 signaling cascades and migration will be tested as targets for novel therapies. In Project 3, David Largaespada will use an innovative transposon insertional mutagenesis strategy in mice to screen for genes that modify peripheral nerve tumorigenesis. Identified genes will lie in signaling pathways that represent next generation targets for therapeutic strategies. All projects use an Administrative Core (Ratner, PI), a Mouse Xenograft Core (Timothy Cripe, PI) and a Pathology Core (Tilat Rizvi, PI). Our long-term goal is to translate research findings into patient therapies. Cincinnati Children's Hospital has an outstanding pediatric NF1 clinic with over 800 patients in its database, has participated in ongoing NF1 clinical trials, and participates in a new OOD NF Clinical Consortium project. It is also a leading center for pediatric anticancer drug development and a member of the NCI's Pediatric Phase I Consortium. Together these projects bring together a world class group of investigators to identify and stratify drugs for use in NF1 treatment, in an environment that can facilitate clinical trials.